10-49642673-G-C

Variant names:

• chr10-49642673-G-C
• rs12358003
• NM_020549.5:c.1112-3832G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020549.5(CHAT):​c.1112-3832G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0961 in 152,322 control chromosomes in the GnomAD database, including 958 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.096 (958 hom., cov: 33)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.439
• Publications: 1 publications found

Genes affected

CHAT (HGNC:1912): (choline O-acetyltransferase) This gene encodes an enzyme which catalyzes the biosynthesis of the neurotransmitter acetylcholine. This gene product is a characteristic feature of cholinergic neurons, and changes in these neurons may explain some of the symptoms of Alzheimer's disease. Polymorphisms in this gene have been associated with Alzheimer's disease and mild cognitive impairment. Mutations in this gene are associated with congenital myasthenic syndrome associated with episodic apnea. Multiple transcript variants encoding different isoforms have been found for this gene, and some of these variants have been shown to encode more than one isoform. [provided by RefSeq, May 2010]

CHAT Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 6

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020549.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	NM_020549.5	MANE Select	c.1112-3832G>C		intron	N/A	NP_065574.4
	CHAT	NM_001142933.2		c.866-3832G>C		intron	N/A	NP_001136405.2
	CHAT	NM_001142929.2		c.758-3832G>C		intron	N/A	NP_001136401.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	ENST00000337653.7	TSL:1 MANE Select	c.1112-3832G>C		intron	N/A	ENSP00000337103.2
	CHAT	ENST00000395562.2	TSL:1	c.866-3832G>C		intron	N/A	ENSP00000378929.2
	CHAT	ENST00000339797.5	TSL:1	c.758-3832G>C		intron	N/A	ENSP00000343486.1

Frequencies

GnomAD3 genomes AF: 0.0962 AC: 14647 AN: 152204 Hom.: 961 Cov.: 33

Gnomad AFR AF: 0.0277

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.0720

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0747

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.0920

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0961 AC: 14640 AN: 152322 Hom.: 958 Cov.: 33 AF XY: 0.0947 AC XY: 7055 AN XY: 74482

African (AFR) AF: 0.0277 AC: 1151 AN: 41588

American (AMR) AF: 0.0719 AC: 1100 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 419 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.0742 AC: 358 AN: 4828

European-Finnish (FIN) AF: 0.144 AC: 1524 AN: 10608

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9719 AN: 68014

Other (OTH) AF: 0.0911 AC: 192 AN: 2108

Alfa AF: 0.120 Hom.: 156

Bravo AF: 0.0880

Asia WGS AF: 0.0330 AC: 116 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.6
DANN	Benign	0.76
PhyloP100		0.44
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12358003; hg19: chr10-50850719;